19-47834451-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_000554.6(CRX):c.8C>T(p.Ala3Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000446 in 1,613,646 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A3A) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000049 ( 0 hom. )
Consequence
CRX
NM_000554.6 missense
NM_000554.6 missense
Scores
3
9
4
Clinical Significance
Conservation
PhyloP100: 5.83
Genes affected
CRX (HGNC:2383): (cone-rod homeobox) The protein encoded by this gene is a photoreceptor-specific transcription factor which plays a role in the differentiation of photoreceptor cells. This homeodomain protein is necessary for the maintenance of normal cone and rod function. Mutations in this gene are associated with photoreceptor degeneration, Leber congenital amaurosis type III and the autosomal dominant cone-rod dystrophy 2. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some variants has not been determined. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM1
?
In a chain Cone-rod homeobox protein (size 298) in uniprot entity CRX_HUMAN there are 56 pathogenic changes around while only 17 benign (77%) in NM_000554.6
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CRX | NM_000554.6 | c.8C>T | p.Ala3Val | missense_variant | 2/4 | ENST00000221996.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CRX | ENST00000221996.12 | c.8C>T | p.Ala3Val | missense_variant | 2/4 | 2 | NM_000554.6 | P1 | |
CRX | ENST00000556527.1 | n.78-1792C>T | intron_variant, non_coding_transcript_variant | 1 | |||||
CRX | ENST00000566686.5 | c.8C>T | p.Ala3Val | missense_variant | 2/3 | 5 | |||
CRX | ENST00000613299.1 | c.8C>T | p.Ala3Val | missense_variant | 2/3 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152144Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251464Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135910
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GnomAD4 exome AF: 0.0000486 AC: 71AN: 1461502Hom.: 0 Cov.: 31 AF XY: 0.0000413 AC XY: 30AN XY: 727102
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Leber congenital amaurosis 7;C3489532:Cone-rod dystrophy 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 18, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3 of the CRX protein (p.Ala3Val). This variant is present in population databases (rs762715327, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with CRX-related conditions. ClinVar contains an entry for this variant (Variation ID: 853189). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CRX protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Retinal dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Dept Of Ophthalmology, Nagoya University | Oct 01, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Pathogenic
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;.;T;T
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;N;N;.
Sift
Uncertain
D;D;D;.
Sift4G
Uncertain
D;D;D;D
Polyphen
0.98
.;D;D;.
Vest4
0.27, 0.35, 0.48
MVP
MPC
0.39
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at